The cerebral cortex has long been recognized as a participant in the overall scheme of autonomic regulation of the cardiovascular system, as clearly evident from studies examining the anticipatory response to physical activity. However, the specific cortical sites and neural mechanisms involved are not well understood. The long-term goal of this line of investigation is to elucidate the cerebral cortical structures and the neural mechanisms involved in the autonomic regulation of cardiovascular function. By activating the cardiovascular system using an exercise model, one can begin to understand how these cortical structures normally function and further study their interactions in the scheme of overall cardiovascular regulation with the arterial baroreflexes, afferent input from working muscle, central motor command, and perception of effort. With a clearer picture of how the cerebral cortex normally functions, patients with known cardiovascular medical problems involving the cerebral cortex, such as stroke-induced cardiac arrhythmia and essential hypertension, will be studied. Current clinical findings indicate that individuals suffering damage to the insular cortex (from stroke or other cerebrovascular trauma) are more prone to develop significant cardiac problems; there are data to suggest that the insular region may be involved in sudden cardiac death, as well as in the pathogenesis of hypertension. State-of-the-art investigations can be performed using single photon emission computed tomography (SPECT) to assess regional cerebral blood flow (rCBF) changes coupled with anatomically precise magnetic resonance imaging (MRI) to ultimately define exact anatomical sites of human brain activation. By comparing rCBF changes between experimental conditions, specific structures and their functions can be identified. This approach has been used to confirm activation of the insular cortex in humans during exercise and further suggest that the right insular cortex may be more related to the regulation of sympathetic outflow, while the left insular cortex may play a greater role in regulation of parasympathetic activity. Specific aims for this proposal have been developed towards delineating the specific roles of cortical regions, as related to autonomic nervous system regulation of the human cardiovascular system during exercise. These studies represent an initial step in furthering the understanding of the role played by the human cerebral cortex in health and disease.